Niemann-Pick human lymphoblasts are resistant to phthalocyanine 4-photodynamic therapy-induced apoptosis

Stress-induced activation of sphingomyelinase (SMase) leading to generation of ceramide, a lipid mediator, has been associated with apoptosis in sever al malignant and nonmalignant cell lines. Photodynamic therapy (PDT), with the phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)(2)(CH2)(3)N(CH3)(2) ], is an oxidative stress associated with increased ceramide generation and subsequent induction of apoptosis in various cell types. We assessed the r ole of SMase in photocytotoxicity. Normal human lymphoblasts accumulated ce ramide and underwent apoptosis after Pc 4-PDT. In contrast, Niemann-Pick di sease (NPD) lymphoblasts, which are deficient in acid sphingomyelinase (ASM ase) activity, failed to respond to Pc 4-PDT with ceramide accumulation and apoptosis, suggesting that ASMase may be a Pc 4-PDT target. NPD lymphoblas ts were exposed to exogenous bacterial sphingomyelinase (bSMase) to test wh ether these defects are reversible. Treatment of NPD cells with bSMase itse lf led to elevated ceramide formation, which did not translate into inducti on of apoptosis, However, a combination of Pc 4-PDT + bSMase induced a sign ificant apoptotic response. Thus, the combined treatment of Pc 4-PDT + bSMa se, rather than bSMase alone, was required to restore apoptosis in NPD cell s. These data support the hypothesis that SMase is a proapoptotic factor de termining responsiveness of cells to Pc 4-PDT, (C) 1999 Academic Press.